Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Green tea polyphenols, major constituents of green tea, are potent chemopreventive agents in a number of experimental models of cancer in animals. The mechanisms of cancer protection by these agents are not clear, but may involve modulation of the enzyme systems responsible for the detoxification of chemical carcinogens. The present studies show that a green tea polyphenol extract (GTP) induces chloramphenicol acetyltransferase (CAT) activity in human heptoma HepG2 cells transfected with a plasmid construct which contains an antioxidant-responsive element (ARE) and a minimal glutathione S-transferase Ya promoter linked to the CAT reporter gene. This indicates that GTP stimulates the transcription of Phase II detoxifying enzymes through the ARE. To explore the upstream signaling pathways leading to gene expression, we studied the involvement of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 2 (ERK2) and c-Jun N-terminal kinase 1 (JNK1). Potent activation of ERK2 was seen following treatment of HepG2 cells with different concentrations of GTP. Similar to ERK2, JNK1 was also strongly activated by treatment with GTP, although to a lesser extent and in a different dose-dependent fashion. Kinetic studies revealed that GTP activation of JNK1 was delayed and sustained, whereas ERK2 activation was rapid and transient. Furthermore, GTP treatment also increased mRNA levels of the immediate-early genes c-jun and c-fos, as determined by reverse transcriptase-coupled polymerase chain reaction. Taken together, these studies provide insights into the action of GTP and suggest that the stimulation MAPKs may be the potential signaling pathways utilized by GTP to activate ARE-dependent genes.
Carcinogenesis 1997 Feb
PMID:Activation of mitogen-activated protein kinases by green tea polyphenols: potential signaling pathways in the regulation of antioxidant-responsive element-mediated phase II enzyme gene expression. 905 42

Retinoids, including retinol and retinoic acid derivatives, inhibit the growth of normal human bronchial epithelial (HBE) cells. Using a lung carcinogenesis model consisting of normal, immortalized, and tumorigenic HBE cells, we showed previously that, compared to normal HBE cells, the tumorigenic HBE cell line 11701 is resistant to the growth-inhibitory effects of all-trans-retinoic acid (t-RA). Retinoid receptor function is preserved in tumorigenic 11701 cells, suggesting that other retinoid signaling components are altered. The activator protein 1 (AP-1) complex is a component of the retinoid signaling pathway and has demonstrated importance in cellular growth and differentiation. Therefore, we investigated whether AP-1 is involved in a retinoid signaling defect in tumorigenic 11701 cells and in retinoid-resistant non-small cell lung cancer (NSCLC) cell lines. We found that t-RA treatment inhibited AP-1 transcriptional activity in normal HBE cells but not in tumorigenic 11701 cells nor in the NSCLC cell lines Calu-1, Calu-6, SKMES-1, and ChaGo K1. We sought mechanisms for this retinoid signaling alteration involving AP-1 in tumorigenic 11701 cells. Basal AP-1 transcriptional activity; AP-1 DNA-binding activity; and the mRNA levels of c-fos, the AP-1 coactivator Jun activation domain-binding protein 1, and the retinoid receptor corepressor, the silencing mediator for retinoid and thyroid hormone receptors (SMRT), were lower in tumorigenic 11701 cells than in normal HBE cells. Transient transfection of tumorigenic 11701 cells with c-fos or CREB binding protein, which is a coactivator of AP-1 and retinoid receptors, enhanced basal AP-1 transcriptional activity but did not alter the effects of t-RA on AP-1 transcriptional activity. These findings provide evidence of a retinoid signaling alteration involving AP-1 in tumorigenic 11701 and NSCLC cells. Furthermore, the inhibitory effect of t-RA on AP-1 transcriptional activity was not restored in tumorigenic 11701 cells by transfection of c-fos, silencing mediator for retinoid and thyroid hormone receptors, Jun activation domain-binding protein 1, or CREB-binding protein, suggesting the involvement of other transcriptional coregulators in this retinoid signaling defect.
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PMID:Evidence of a retinoid signaling alteration involving the activator protein 1 complex in tumorigenic human bronchial epithelial cells and non-small cell lung cancer cells. 905 70

Manganese superoxide dismutase (MnSOD) has been found to be depleted in a variety of tumor cells as well as in in vitro transformed cell lines, suggesting that MnSOD may function as an anticarcinogen by protecting the cell from oxidant-induced carcinogenesis. The relationship between MnSOD expression and tumor promotion was studied by transfection of a human MnSOD cDNA into the promotable mouse epidermal cell line JB6 clone41. The effect of MnSOD overexpression on the promotion-sensitive phenotype of JB6 cells was assessed by measuring growth characteristics such as growth rate and the ability to form colonies in soft agar. Compared with the parental and vector-transfected (gpt) control cells, MnSOD-overexpressing cells had a slower growth rate and their ability to form colonies in soft agar was significantly decreased in response to 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. Since the transformation-sensitive phenotype of JB6 clone41 cells is associated with increased expression of the transcription factor AP-1, we compared c-jun and c-fos mRNA expression in MnSOD-transfected and control JB6 cells. Overexpression of MnSOD led to a significant decrease in c-jun and c-fos expression in response to treatment with TPA or the oxidant promoter superoxide. These findings indicate that the promotion-sensitive phenotype of JB6 clone41 cells can be reverted by increasing MnSOD intracellularly. A possible mechanism is that elevated MnSOD expression might change the intracellular redox state by altering the balance of reactive oxygen species. This could lead to a modulation of TPA and oxidant-induced signal transduction pathways controlling cell growth and differentiation.
Carcinogenesis 1997 Mar
PMID:Manganese superoxide dismutase expression inhibits soft agar growth in JB6 clone41 mouse epidermal cells. 906 45

The hematotoxicity of benzene, a human leukemogen, has been postulated to be mediated by reactive metabolites and involve cell damage caused by reactive oxygen species. Because expression of the transcription factors AP-1 and NF-kappaB is sensitive to the redox state in eukaryotic cells, the DNA binding activity of AP-1 and NF-kappaB was examined in HL-60 promyeloid leukemia cells exposed to trans,trans-muconaldehyde, a microsomal hematotoxic metabolite of benzene. There was little AP-1 binding activity in nuclear extracts from control HL-60 cells based on electrophoretic mobility shift assays. Exposure to 0.1 microM MUC for 4 h resulted in significantly increased levels of nuclear protein with high sequence specificity for the consensus AP-1 sequence. In addition, electrophoretic mobility shift assays showed a strong increase in the binding of a factor to the NF-kappaB site. The latter was highest in nuclear extracts from HL-60 cells treated with 1.0 microM muconaldehyde and cultured for 4 h. Exposure of HL-60 cells to muconaldehyde resulted in an increase in c-fos and c-jun mRNA levels. Western blot analysis showed that the protein levels of c-jun increased in HL-60 cells treated with 1 microM muconaldehyde and cultured for 4-6 h and subsequently decreased gradually. Increased AP-1 binding was observed in bone marrow cells from B6C3F1 mice 2 h after administration of 440 mg/kg benzene. We suggest that increased gene expression of NF-kappaB and AP-1 binding activity and up-regulation of c-fos and c-jun may play a role in the mechanism of benzene leukemogenesis.
Carcinogenesis 1997 Apr
PMID:Increased gene expression in human promyeloid leukemia cells exposed to trans,trans-muconaldehyde, a hematotoxic benzene metabolite. 911 Dec 8

DNA damage is recognized as a central component of carcinogenesis. DNA-damaging agents activate a number of signal transduction pathways that lead to repair of the DNA, apoptosis, or cell cycle arrest. It is reasoned that a cell deficient in DNA repair is more likely to acquire other cancer-promoting mutations. Despite the recent interest in the link between DNA damage and carcinogenesis, retroviral oncogenes have not yet been shown to affect the DNA damage-signaling pathway. In this report, we show that Finkel-Biskis-Reilly mouse osteosarcoma virus (FBR) v-fos, the retroviral homologue of the c-fos proto-oncogene, inhibits the cellular response to ionizing radiation. Cells that express FBR v-Fos show a decreased ability to repair DNA damage caused by ionizing radiation, and these cells show decreased survival in response to ionizing radiation. In addition, FBR v-Fos inhibits DNA-dependent protein kinase, a kinase specifically activated upon exposure to ionizing radiation. These effects were specific to ionizing radiation, as no effect of FBR v-Fos on the UV light signaling pathway was seen. Last, these effects were dependent on a lipid modification required for FBR v-Fos tumorigenesis, that of myristoylation of FBR v-Fos. A non-myristoylated mutant FBR v-Fos caused none of these effects. This study suggests that a retroviral oncogene can lead to an increased genomic instability, which can ultimately increase the carcinogenic potential of a cell.
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PMID:Finkel-Biskis-Reilly mouse osteosarcoma virus v-fos inhibits the cellular response to ionizing radiation in a myristoylation-dependent manner. 916 16

Cytoskeleton not only controls cell morphology but also regulates cell growth, migration, differentiation, and gene expression, events which are fundamental to embryogenesis, carcinogenesis, and wound healing. We have recently reported that reorganization of cytoskeleton induces expression of mRNA for transforming growth factor-beta 1 (TGF-beta 1), collagenase, and tissue inhibitor of metalloproteinase-I (TIMP-I) in dermal fibroblasts. In this report we have examined the role of gene transcription in this induction. As judged by nuclear run-on assay, trypsin, EGTA (ethylene glycol-bis (beta-aminoethyl ether) N, N, N', N', tetra-acetic acid), or cytochalasin C (Chs) increased the rate of transcription of the TGF-beta 1 gene by 2.0, 2.7, and 1.6 fold, respectively, and of the collagenase gene by 5.3, 6.2, and 3.3 fold. The rate of transcription of the TIMP-I gene was increased by trypsin (4.3 fold) or EGTA (3.8 fold) but unaffected by Chs. Cytochalasin induced an increase in the rate of transcription of procollagen I (alpha 1), procollagen I (alpha 2), and fibronectin genes by 1.4, 1.5, and 1.9 fold respectively, while trypsinization or EGTA treatment had no or little effects on these gene. Since transcription of the TGF-beta 1 gene is believed to be largely governed by the activating protein 1 (AP1) complex, we also examined the expression of mRNA for c-fos and c-jun protoon-coproteins. Trypsinization induced rapid (within 30 min) and transient expression of c-fos mRNA. A 2.4 fold increase in c-jun mRNA was apparent after 4 hr and persisted for at least 24 hr. Actinomycin D (Act D) suppressed the induction of TGF-beta 1 mRNA by Chs but had less effect on the TGF-beta 1 mRNA in trypsinized cells which had been replated for 4 hr, suggesting that the half life of TGF-beta 1 mRNA is reduced in cells with a disassembled cytoskeleton. Simultaneous treatment with Chs and cycloheximide (Cxm) resulted in a superinduction of TGF-beta 1 mRNA by 88 +/- 23% (n = 4, P < 0.05), which was abrogated by preexposure to Act D. In contrast, the induction of collagenase mRNA by Chs was totally blocked by Cxm, indicating that the Cxm-mediated superinduction is selective and that protein synthesis is required for induction of this mRNA. Our results suggest that the activities of genes for proteins involved in the structure (Type I collagen and fibronectin), turnover (collagenase and TIMP-1) and regulation (TGF-beta 1) of extracellular matrix (ECM), are all governed at least in part by the status of the cytoskeleton. Since the cytoskeleton is reorganized during cell division, migration, and differentiation, these results may have implications for the regulation of ECM during such processes as embryogenesis, carcinogenesis, and wound healing.
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PMID:Cytoskeleton regulates expression of genes for transforming growth factor-beta 1 and extracellular matrix proteins in dermal fibroblasts. 925 40

Aflatoxin B1 (AFB1), a fungal toxin produced by Aspergillus flavus, is known to be a possible hepatocarcinogen. But the molecular biologic changes which may occur following exposure to AFB1 are not known and thus the carcinogenesis is not yet understood. This study was performed to examine the expressions of c-myc, c-fos and TGF-alpha genes and to investigate the possible role of those molecular biologic changes in hepatic regeneration and in the development of hepatocellular carcinoma (HCC). Sprague-Dawley rats were divided into 3 groups: Carbon tetrachloride (CCl4) only was administered to group I, AFB1 only was administered to group II and a combination of AFB1 and CCl4 was administered to group III. The animals were sacrificed at 0.5, 1, 2, 6, 12, 24, 48, and 72 hours after treatment. In addition to the examination of the hematoxylin-eosin stained sections, hepatic regeneration and apoptosis were analyzed quantitatively by bromodeoxyuridine (BrdU)-anti-BrdU immunohistochemistry and TUNEL assay utilizing apoptosis kit, respectively. The hepatic expressions of c-myc, c-fos and transforming growth factor-alpha (TGF-alpha) were examined by immunohistochemistry and studied by Western blot. The number of BrdU labelled cells and the degree of necrosis/apoptosis were comparable among the different groups. Livers of the group II rats showed nearly normal histology without regeneration and necrosis/apoptosis. In groups I and III, the number of BrdU- labelled cells showed an increase at 48 hours after treatment, and the increment was significantly higher in group I than in group III. Most BrdU-labelled cells were mature hepatocytes in group I, whereas in group III they appeared to be less mature. In group I, apoptosis showed an increase at around 24 hours, but appeared in group III as early as 12 hours after treatment and persisted through 48 hours. The expression of c-myc and c-fos were also different between the experimental groups. The expression intensity of c-myc in group I was highest at 1 hour and decreased thereafter. In groups II and III, the expressions were much more intense than in group I, except at 1 hour, and the increased intensity persisted throughout the experiment. Group II in particular showed a peak intensity at 30 minutes and at 6 hours after treatment. In group I, c-fos was strongly expressed only at 24 hours, but in group III, there was progressively increased expression with peak intensity at 24 hours. TGF-alpha was expressed in similar intensities in all groups throughout the experiment. These results suggest that AFB1 may evoke an intense and protracted expression of c-myc, provocating the CCl4-induced necrosis of hepatocytes, and a prolonged expression of c-fos, including persistent signals for regeneration which in turn may activate the replication of immature cells. These findings will aid further investigation of molecular biologic and histologic characteristics of the hepatotoxic and hepatocarcinogenic mechanism of AFB1 in rats. And these results in rats, together with clinico-epidemiologic and molecular biologic investigations in humans and other animals, suggest that AFB1 may supply hepatocarcinogenic background in early exposure time in AFB1-contaminated areas of China and Korea.
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PMID:The effect of aflatoxin B1 on the expression of early response genes and transforming growth factor-alpha in CCl4 induced rat liver injury. 925 17

Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are metabolites of the industrial solvent and environmental contaminant trichloroethylene (TCE), as well as contaminants of chlorinated drinking water. Human exposure to these chemicals is of concern as all three have been shown to increase liver tumor incidence in mice. Differences in dose-response curves, progression to cancer, and postexposure regression of lesions suggest that TCA and DCA work through different mechanisms. The purpose of this study was to further characterize the proliferative hepatocellular lesions promoted by TCA and DCA using biomarkers of cell growth, differentiation, and metabolism in liver sections to better delineate the distinctions in the mechanism of the two chloroacetates. Fifteen-day-old female mice were initiated with 25 mg/kg N-methyl-N-nitrosourea. The initiated mice were administered DCA or TCA (20.0 mmol/L) in drinking water from age 49 days until euthanasia at age 413 days. The pathologic assessment showed that the foci of altered hepatocytes and tumors occurring in the animals promoted with DCA were eosinophilic and positive immunohistochemically for TGF-alpha, c-jun, c-myc, CYP 2E1, CYP 4A1, and glutathione S-transferase-pi (GST-pi). The DCA lesions also were essentially negative for c-fos and TGF-beta, but nontumor hepatocytes were consistently TGF-beta-positive. In contrast, tumors promoted by TCA were predominantly basophilic, lacked GST-pi, and stained variably; usually, more than 50% of the tumor hepatocytes were essentially negative for the other biomarkers. This study demonstrates some striking differences in certain molecular biomarkers of cell growth, differentiation, and metabolism between DCA and TCA. The results also suggest some potential growth signal transduction pathways that may contribute to the DCA promotion of tumors, further support the premise that these two chloroacetates promote hepatocarcinogenesis in different ways, and provide a rational basis for a similar comparison with TCE. Such a comparison should give some insight as to whether DCA, TCA, or both are playing a significant role in the murine liver carcinogenesis of the parent compound, TCE.
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PMID:Dissimilar characteristics of N-methyl-N-nitrosourea-initiated foci and tumors promoted by dichloroacetic acid or trichloroacetic acid in the liver of female B6C3F1 mice. 932 30

It has recently been reported that new vitamin D3 derivatives can exert inhibitory effects on colon carcinogenesis in rats. In the present study the chemopreventive potential of 24R,25-dihydroxyvitamin D3 (24R,25(OH)2vitamin D3) was assessed in a murine model of colon carcinogenesis. In experiment 1, male 6-week-old F344 rats were administered N,N'-dimethylhydrazine (DMH) 20 mg/kg s.c. once a week 4 times. The rats were fed 24R,25(OH)2vitamin D3 at 10 ppm in the diet prior to (pre), together with (simultaneous) or after (post) DMH treatment. Modifying effects were assessed using aberrant crypt foci (ACF), putative preneoplastic lesions, as the end point markers in this model of colon carcinogenesis. After 8 weeks, pre and more markedly simultaneous administration of 24R,25(OH)2vitamin D3 was found to have reduced the total numbers of ACF and significantly inhibited the development of foci. After 16 weeks, numbers of foci with > or = 4 crypts, which are more likely to progress to tumors, were significantly reduced. The most pronounced inhibition of ACF development was noted in rats fed the 24R,25(OH)2vitamin D3 after DMH administration. The reduction was particularly marked in the proximal colon. Blood levels of calcium were not significantly increased over the control levels in groups administered DMH and the vitamin. Immunohistochemical staining showed numbers of proliferating cell nuclear antigen-positive cells to be lower in the colonic epithelia of rats fed the vitamin D3 metabolite than in the controls. In experiment 2, the effect of 24R,25(OH)2vitamin D3 on the alterations in c-fos, c-myc and c-jun oncogene expression in response to DMH administration was examined by northern blot analysis. The early increase in expression of ornithine decarboxylase (ODC) activity was not altered by 24R,25(OH)2vitamin D3. The results suggest that 24R,25(OH)2vitamin D3 is a cancer chemopreventive agent which may suppresses DMH induction of lesions and their subsequent development via an antiproliferative action.
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PMID:Inhibition of development of N,N'-dimethylhydrazine-induced rat colonic aberrant crypt foci by pre, post and simultaneous treatments with 24R,25-dihydroxyvitamin D3. 943 80

Reactive oxygen species (ROS) are important second messengers for the induction of several genes in a variety of physiological and pathological conditions. Ultraviolet B (UVB) irradiation has recently been shown to generate lipid peroxidation products and hydroxyl radicals (HO.) with detrimental long term effects like cancer formation and premature aging of the skin. Here, we addressed the question of whether ferric/ferrous iron via the generation of ROS may mediate the UVB response, finally leading to connective tissue degradation, a hallmark in carcinogenesis and aging. Therefore, we studied the involvement of iron and ROS in the modulation of Jun N-terminal kinase 2 (JNK2) activity, c-jun and c-fos mRNA levels, key signaling steps in the transcriptional control of matrix-degrading metalloprotease (MMP)-1/interstitial collagenase and MMP-3/stromelysin-1 after UVB irradiation of human dermal fibroblasts in vitro. The iron-driven generation of lipid peroxides and hydroxyl radicals were identified as early events in the downstream signaling pathway of the UVB response leading to a 15-fold increase in JNK2 activity, a 3.5-fold increase in c-jun, to a 6-fold increase in MMP-1, and a 3.8-fold increase in MMP-3 mRNA levels, while virtually no alteration of c-fos mRNA levels were observed. Diminished generation of reactive oxygen species resulted in a significant reduction of JNK2 activity, c-jun, MMP-1, and MMP-3 mRNA levels after UVB irradiation compared with UVB-irradiated cells. Collectively, we have identified the iron-driven Fenton reaction and lipid peroxidation as possible central mechanisms underlying signal transduction of the UVB response.
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PMID:Central role of Ferrous/Ferric iron in the ultraviolet B irradiation-mediated signaling pathway leading to increased interstitial collagenase (matrix-degrading metalloprotease (MMP)-1) and stromelysin-1 (MMP-3) mRNA levels in cultured human dermal fibroblasts. 947 85


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